Cerebral palsy in very preterm infants: new epidemiological insights

The focus of this review is on new insights from recent epidemiological research on cerebral palsy in preterm infants. These include: 1) a better understanding of issues related to diagnosis and classification; 2) new information about the brain abnormalities underlying cerebral palsy in preterm infants; and 3) a better understanding of biological mechanisms that may underlie previously described epidemiological associations. Ongoing efforts to improve the diagnosis and classification of cerebral palsy have been enhanced by findings from serial examinations of cohorts of very preterm infants. Cranial ultrasonography through the anterior fontanelle of very preterm infants has provided information about grossly evident brain damage, found in about one-half of preterm infants who develop cerebral palsy. Insights into the pathophysiologic basis for certain epidemiologic associations have come from studies of experimental brain damage in animals and clinical studies of neurologic disorders in adults. Much of the current epidemiological research into the causes of cerebral palsy in preterm infants has focused on two potential mechanisms of brain damage. One mechanism involves insufficient cerebral perfusion; the other, cytokine-mediated damage, potentially triggered by events such as maternal infection (e.g., intrauterine or periodontal infection), neonatal infection (e.g., sepsis and necrotizing enterocolitis), and neonatal oxygen- or ventilator-induced lung injury. In addition to the preterm infant's increased exposure to such damaging factors, the high frequency of cerebral palsy in these infants might be due, in part, to insufficient levels of developmentally regulated protective substances, such as thyroid hormone and glucocorticoids. Models of causation currently are being investigated using recently developed methods for quantifying, with small quantities of blood, biomolecules that are suspected to either promote or protect against brain damage in the neonate. Clinical investigations now under way can be expected to identify strategies to be tested in clinical trials that could lower the risk of cerebral palsy in very preterm infants.     

Infection markers and early signs of neonatal encephalopathy in the term infant

Recent evidence points to an association between intrauterine infection and cerebral palsy (CP) in the preterm as well as the term infant. The mechanisms that link these two conditions are unclear. Chorioamnionitis is a common clinical problem complicating 5-10% of pregnancies, whereas the incidence of CP attributed to intrapartum asphyxia is rare. Chorioamnionitis may result in brain injury as a result of interruption of placental blood flow (asphyxia), or via fever and/ or the cytokine release associated with infection. This review will attempt to establish the link between perinatal infection and brain damage in term infants. The characteristics of the perinatal inflammatory response, the potential mechanisms of brain injury associated with infection, and the clinical characteristics of neonatal encephalopathy will be discussed.     

Patterns of motor disability in very preterm children

Motor development in very preterm children differs in several important ways from that of children born at full term. Variability is common, although the anatomic and physiologic bases for that variability are often poorly understood. Motor patterns over the first postnatal year may depend on behaviours learned during often long periods of neonatal intensive care. The normal pattern of development may be modified by disturbances of brain function caused both by the interruption of normal brain maturation ex-utero and the superimposition of focal brain injuries following very preterm birth. Abnormal patterns of development over the first year may evolve into clear neuromotor patterns of cerebral palsy or resolve, as "transient dystonias." Cerebral palsy is associated with identified patterns of brain injury secondary to ischaemic or haemorrhagic lesions, perhaps modified by activation of inflammatory cytokines. Cerebral palsy rates have not fallen as might be expected over the past 10 years as survival has improved, perhaps because of increasing survival at low gestations, which is associated with the highest prevalence of cerebral palsy. Children who escape cerebral palsy are also at risk of motor impairments during the school years. The relationship of these impairments to perinatal factors or to neurological progress over the first postnatal year is debated. Neuromotor abnormalities are the most frequent of the "hidden disabilities" among ex-preterm children and are thus frequently associated with poorer cognitive ability and attention deficit disorders. Interventions to prevent cerebral palsy or to reduce these late disabilities in very preterm children are needed.     

The epidemiology of cerebral palsy in term infants

Half of cerebral palsy (CP) arises in infants of normal birthweight; yet, many fewer studies seek to identify risk factors for CP in term and near-term infants than in those born very prematurely. There has been no net decrease in the prevalence of CP in term and near-term infants over recent decades. Potentially asphyxiating birth complications account for a small minority of CP cases. Recent studies suggest that disorders of coagulation and intrauterine exposure to infection or inflammation are associated with risk of CP, and that both can be accompanied by signs of neonatal encephalopathy, the best available predictor of CP in term neonates. Therapeutic interventions directed at preventing interruption of oxygen supply have not been shown to reduce the occurrence of CP. There have not yet been studies examining whether medical interventions directed at infection or coagulation disorder can reduce the frequency of CP.     

Macropremies: underprivileged newborns

The focus of neonatal intensive care has been on very low birthweight infants, who comprise only 1.4% of neonates. Too little attention is paid to moderately preterm infants that we call macropremies or moderately low birthweight infants (MLBW, with birthweights 1500-2500 grams). Admitting over half MLBW infants to normal nurseries presumes that they have few needs and an excellent prognosis similar to fullterm newborns. It does not take into account the macropremie's vulnerability to complications of prematurity due to immature organ systems. Obstetricians are increasingly willing to deliver these infants prematurely for signs of fetal distress. As many as 25% of children with cerebral palsy referred to a disability clinic in Paris were MLBW, with hypoxic-ischemic-inflammatory associated disorders in one-third. The majority of MLBW infants who required neonatal intensive care at a tertiary care center in Baltimore had complications of prematurity: 47% had respiratory problems, 20% had feeding intolerance and 9% had hypoglycemia. MLBW infants comprise 5-7% of the neonatal population but account for 14% of neonatal deaths, 18-37% of children with cerebral palsy and 7-12% of children with mental retardation. Increasing the level of neonatal care for the macropremie's transition to extrauterine life would be economically feasible if it prevented as few as 30% of cases of major disability. A change in attitude towards this low risk (but not risk free) group of MLBW infants will both reduce morbidity and improve their health and neurodevelopmental outcome. It includes: 1) Providing an intermediate level of neonatal care for a short duration, with close monitoring and prompt intervention as needed, and 2) Neonatal neurodevelopmental screening to allow focused neurodevelopmental followup of MLBW infants with abnormalities.     

Preterm outcomes research: a critical component of neonatal intensive care

While early preterm outcome studies described the lives of preterm survivors to justify the efforts required to save them, subsequent studies demonstrated their increased incidence of cerebral palsy, mental retardation, sensory impairments, minor neuromotor dysfunction, language delays, visual-perceptual disorders, learning disability and behavior problems compared to fullterm controls. Because infants born at the lower limit of viability require the most resources and have the highest incidence of neurodevelopmental disability, there is concern that resources have gone primarily to neonatal intensive care and are not available for meeting the followup, health, educational and emotional needs of these fragile infants and their families. Despite many methodological concerns, preterm outcome studies have provided insight into risk factors for and causes of CNS injury in preterm infants. Nevertheless, it remains difficult to predict neurodevelopmental outcome for individual preterm infants. Perinatal and neonatal risk factors are inadequate proxies for neurodevelopmental disability. Recent randomized controlled trials with one to five year neurodevelopmental followup have provided valuable information about perinatal and neonatal treatments. Recognizing adverse longterm neurodevelopmental effects of pharmacological doses of postnatal steroids is a sobering reminder of the need for longterm neurodevelopmental followup in all neonatal randomized controlled trials. Ongoing longterm preterm neurodevelopmental studies, analysis of changes in outcomes over time and among centers, and evaluation of the longterm safety, efficacy and effectiveness of many perinatal and neonatal management strategies and proposed neuroprotective agents are all necessary for further medical and technological advances in neonatal intensive care.     

Intrauterine infection and prematurity

Intrauterine infection is a major cause of premature labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm births and the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection. Microorganisms may also gain access to the fetus before delivery. A fetal inflammatory response syndrome elicited in response to microbial products is associated with the impending onset of preterm labor and also with multi-systemic organ involvement in the human fetus and a higher rate of perinatal morbidity. The most common microorganisms involved in intrauterine infections are Ureaplasma urealyticum, Fusobacterium species and Mycoplasma hominis. The role of Chlamydia trachomatis and viruses in preterm labor remain to be determined. Use of molecular microbiology techniques to diagnose intrauterine infection may uncover the role of fastidious microorganisms that have not yet been discovered. Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm birth. However, such benefit has not been demonstrated for patients with bacterial vaginosis, or women who carry Streptococcus agalactia, Ureaplasma urealyticum or Trichomonas vaginalis. Antibiotic administration to patients with preterm premature rupture of membranes is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. The benefit has not been demonstrated in patients with preterm labor and intact membranes. Major efforts are required to determine why some women develop an ascending intrauterine infection and others do not and also what interventions may reduce the deleterious effect of systemic fetal inflammation.     

Health and educational outcomes of children who experienced severe neonatal medical complications.

To determine the long-term developmental and educational outcomes of a sample of low birthweight infants with intraventricular hemorrhage (IVH), the authors conducted developmental assessments and interviews 8 years after the initiation of an early intervention project. At the time of the follow-up, 62% of the children were experiencing some developmental or behavior problems, with visual impairments, cerebral palsy, and attention deficits occurring most frequently. Grade of IVH and the number of days spent in the neonatal intensive care unit were the best predictors of later developmental delays. The sample also scored below average on school achievement; approximately 30% of those in school were eligible for special education services. These findings corroborate results from investigations with similar populations whose birth characteristics put them at risk for subsequent developmental delay.     

Stability of developmental status and risk of impairment at 24 and 36 months in late preterm infants

BackgroundFew studies investigated whether late preterm infants might have developmental delays in several domains in early life and how stable the lag in developmental status might be.AimWe aimed to examine the stability of potential delays across developmental domains at 24 and 36 months of age in late preterm (34°-36⁶ weeks) and term (≥37 weeks) children and whether the risk of delays remained high at 36 months.Study design, subjects, and outcome measureWe conducted a prospective cohort analysis of the children of pregnant women participating in the Vitamin Antenatal Asthma Reduction Trial (VDAART). 652 children who were prospectively followed up and had parent-completed Ages Stages Questionnaires (ASQ-3) questionnaires at both 24 and 36 months were analyzed to assess their domain-specific developmental status.Results6.61 % (42/635) of children had a late preterm birth. Developmental delays were stable between 24 and 36 months on all 5 domains for the children born preterm and on 4/5 domains for those born at term. The developmental domains with the status stability at 24 and 36 months in both late preterm and term children were the gross motor, communication, personal-social skills, and problem-solving. Late preterm children compared with term children remained at higher risk of delays at 36 months for gross motor, communication, and problem-solving skills (aOR = 4.54, 95 %CI: 1.81−10.79; aOR = 8.60, 95 %CI: 3.10−23.28 and aOR = 3.80, 95 %CI: 1.58−8.73, respectively).ConclusionLate preterm birth is associated with suboptimal development and stability in several domains at both 24 and 36 months and compared with term birth, requiring early monitoring and assessment of the developmental lag to avoid potential long-term implications.     

Systematic review of chorioamnionitis and cerebral palsy

In a recent meta-analysis evaluating the relationship between chorioamnionitis and cerebral palsy, we found that chorioamnionitis is a risk factor for both cerebral palsy and cystic periventricular leukomalacia (cPVL). The current paper extends the meta-analysis by including studies published in the year 2000, and by further evaluating the causes of heterogeneity among individual study results. Using a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR 1.9, 95% CI 1.5-2.5) and cPVL (RR 2.6, 95% CI 1.7-3.9). Sources of heterogeneity included widely varying practices in the diagnosis of clinical chorioamnionitis, different gestational age characteristics, and varying study year. We conclude that based on the available literature, chorioamnionitis is a risk factor for both cerebral palsy and cPVL.     

Developmental effects of an intervention for preterm infants of teenage mothers

Since preterm infants and infants born to teenage mothers are noted to be at risk for developmental delays, a group of infants who were both preterm and born to teenage mothers was provided a sensorimotor exercise intervention program for the first year of infancy. The development of these infants was compared to the development of preterm infants without intervention and term infants of teenage mothers as well as term and preterm infants of adult mothers to determine the degree to which developmental delays were prevented. The intervention infants showed more optimal growth, cognitive development, temperament and play behaviors during interactions with their mothers across the first year of development.     

Prem Baby Triple P a new parenting intervention for parents of infants born very preterm: acceptability and barriers

Over 10% of preterm infants develop major disabilities, 50% develop behavioural problems and 40% need special education ( [Huddy et al., 2001] and [0185] ). Prem Baby Triple P is a new variant of the Positive Parenting Program (Triple P) adapted specifically for parents of very preterm infants. The aim of this study is to assess the acceptability of Prem Baby Triple P to parents of infants born preterm and to test whether parental attributions and parental perception of infant health/developmental status are barriers to intervention acceptability. One hundred and twenty-three parents of preterm infants participated, 83 parents of very preterm infants and 40 parents of preterm infants. In addition, 32 parents of term infants participated as a comparison group. The acceptability of Prem Baby Triple P was moderately high and did not differ significantly across the three groups. Parental attributions were not found to be barriers to intervention acceptability and parental perceptions that their infant is less healthy/developmentally delayed facilitated Prem Baby Triple P acceptance in parents of infants born very preterm. This suggests that the planned Prem Baby Triple P content is acceptable to parents of infants born very preterm and sensitised to medical and developmental issues. These findings, as social validation data, will contribute towards the further development of Prem Baby Triple P and a future randomised controlled trial.     

Relations between neonatal states and 8-month developmental outcome in preterm infants

This study investigated longitudinal relations between measures of neonatal state behavior and developmental outcome in a sample of preterm infants (N = 16). Results indicate that irritability/reactivity in the neonatal period is positively associated with Bayley scores and exploratory play at 8 months. Conversely, neonatal alertness was not associated with these developmental measures. These preliminary findings, based on a small sample, are discussed in the context of preterm function.     

Late Preterm Birth: A Review of Medical and Neuropsychological Childhood Outcomes

Late preterm (LP) birth (34 0/7 - 36 6/7 weeks?? gestation) accounts for nearly three-fourths of all preterm births, making this population a sizeable public health concern. The immature fetal development associated with LP delivery increases the risk of mortality and short-term medical complications. Which combination of maternal, fetal, or neonatal risk factors may be most critical has only recently begun to be addressed, and whether LP birth??s disruptive impact on brain development will exert adverse effects on neuropsychological functioning in childhood and adolescence has been understudied. Early data have shown a graded response, with LP children often functioning better than very preterm children but worse than term children, and with subtle intellectual and neuropsychological deficits in LP children compared with healthy children born at term gestational age. Further characterization of the neuropsychological profile is required and would be best accomplished through prospective longitudinal studies. Moreover, since moderate and LP births result in disparate medical and psychological outcomes, the common methodology of combining these participants into a single research cohort to assess risk and outcome should be reconsidered. The rapidly growing LP outcomes literature reinforces a critical principle: fetal development occurs along a dynamic maturational continuum from conception to birth, with each successive gestational day likely to improve overall outcome.     

Gaze aversion during social interaction in preterm infants: a function of attention skills?

Preterm infants avert their gaze more often and for longer periods in early social interactions compared to full term infants. In previous studies this finding is interpreted as being a function of the higher degree of parental stimulation that is often found in parents of preterm children. The current study explores an additional hypothesis. Since the development of general visual attention abilities is found to be less optimal in preterm children, it is possible that less optimal maturation of attention abilities partially explains the elevated gaze aversion in a social context. Therefore, the current study investigated the association between gaze aversion in a social context and the ability to disengage and shift visual attention in a non-social context in 20 preterm and 42 full term infants aged 4 and 6 months. Results confirm that preterm infants are slower to shift their attention in a non-social context and that they avert their gaze more often in a social context compared to full term children. Furthermore, more frequent gaze aversion during social interaction at 6 months was related to longer disengagement and the shifting of attention at 4 and 6 months, but only within the preterm group. The results suggest that attention maturation is less optimal in preterm children; this can be observed in a non-social as well as a social context. Less attention maturation in preterm children can negatively influence the amount of time they can stay actively involved in social interaction.     

Psychiatric diagnoses of infants and toddlers referred to a community mental health system

There has been increased interest in improving mental health assessment and treatment of young children. However, there are limited data regarding the prevalence of psychiatric disorders among infants and toddlers. The recent development of measures and classification systems that are specific to this age group has enabled researchers to begin to investigate the social, emotional, and behavioral problems of young children. The present study reviews the major research that has been conducted in this area and examines the prevalence of psychiatric diagnoses of infants and toddlers referred to a public community mental health system. The current investigation also compares the frequency of diagnoses of children who have been evaluated based on the Diagnostic and Statistical Manual (4th edition) with another group of children who were diagnosed based on the Diagnostic Classification: 0-3 system. Although there were some differences between the two samples and classification systems, analysis indicated that parent-child relational problems, adjustment difficulties, regulatory problems, and developmental disorders are some of the more common diagnoses prevalent among young children referred for outpatient treatment. As diagnostic measures and classification systems continue to improve, clinicians will have a better understanding of the mental health problems and treatment needs of young children.     

Effect of developmental care for very premature infants on neurodevelopmental outcome at 2 years of age

BackgroundTo determine the effect of developmental care on neurodevelopmental outcome in formerly preterm infants at a corrected age of 2 years.MethodsA prospective phase-lag study was performed at an Austrian neonatal intensive care unit (NICU). From January 2003 to December 2005 (study period of conventional care) and January 2007 to December 2009 (study period of developmental care), we enrolled all infants born in Tyrol at less than 32 weeks of gestation. During this period a total of 261 of 359 preterm infants (participation rate 72.7%) completed the follow-up visit at 2 years of age; there were 124 children in the conventional and 137 in the developmental care group. The association between developmental care and delayed motor or mental development (Bayley Scales of Infant Development II; psychomotor or mental developmental index <85) was analyzed by means of logistic regression analysis at a corrected age of 24 months.ResultsChildren in the developmental care group showed less psychomotor delay than did those in the control group (developmental care group: 16.1%, conventional care group 27.4%; adjusted odds ratio 0.37 [95% confidence interval: 0.19–0.74], P = 0.005). Not smoking in pregnancy and higher gestational age were also significant predictors for a better psychomotor outcome at 2 years of age. Regarding cognitive outcome, no significant difference was observed between these two groups.ConclusionOur data implicate that developmental care may result in an improved 2-year psychomotor outcome in formerly preterm infants.     

Dyadic and triadic skills in preterm and full term infants: a longitudinal study in the first year

This longitudinal study examined dyadic and triadic skills in 26 preterm and 31 full term infants at 3, 6 and 9 months of age. In dyadic interaction, infants engaged with a stranger in face-to-face play interrupted by a still-face episode. In triadic interaction, infants interacted with the adult stranger as she coordinated gaze between the infant and object. Both groups were sensitive for non-contingency in both dyadic and triadic interactions. There were significant group and developmental differences for dyadic and triadic competencies. Compared to full term infants, preterms made less positive elicits during the still-face at 6 months and followed gaze less at 9 months of age. Six-month dyadic skills and 9-month triadic competencies were positively related in preterm and full term infants.     

Ophthalmological,cognitive, electrophysiological and MRI assessment of visual processing in preterm children without major neuromotor impairment

Many studies report chronic deficits in visual processing in children born preterm. We investigated whether functional abnormalities in visual processing exist in children born preterm but without major neuromotor impairment (i.e. cerebral palsy). Twelve such children (< 33 weeks gestation or birthweight < 1000 g) without major neuromotor impairment and 12 born full‐term controls were assessed at 8–12 years of age by means of ophthalmological assessment (visual acuity, colour vision, stereopsis, stereoacuity, visual fields, ocular motility, motor fusion), cognitive tests of visual‐motor, visual‐perceptual and visual‐spatial skills and pattern‐reversal visual evoked potentials (PR‐VEPs). All participants also underwent magnetic resonance imaging (MRI) of the brain and neuromotor assessments. No significant differences were found between the groups on the ophthalmological, visual cognitive, neurological, neuromotor or MRI measures. The P100 component of the PR‐VEP showed a significantly shorter latency in the preterm compared with the full‐term participants. Whilst this P100 finding suggests that subtle abnormalities may exist at the neurophysiological level, we conclude that visual dysfunction is not systematically associated with preterm birth in the context of normal neurological status.     

Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm

Only sparse information is available about a possible association between antenatal infection outside the brain and subsequent cognitive limitations among preterm infants. Based on published studies, we provide a theoretical schema that links them via the fetal inflammatory response and neonatal white matter damage. We conclude that the relationship between antenatal infection and cognitive limitations deserves much further attention by researchers interested in the prevention of this undesirable outcome of prematurity.